1. Field of the Invention
The present invention is in the fields of medicine, pharmaceuticals, neutraceuticals and rheumatology. In one aspect, the invention is related to the use of compositions comprising sodium bicarbonate and calcium gluconate in methods for the treatment and/or prevention of osteoarthritis, and to the use of such compositions in the manufacture of products for such treatment and/or prevention.
2. Related Art
Osteoarthritis
Osteoarthritis (OA) is the most common joint disease in mammals and is characterized by a progressive loss of articular cartilage components, mainly proteoglycans. Over time, articular cartilage in OA has been shown to lose its mechanical resistance, elasticity and smoothness, and to be consequently worn out by the movements of the joint. This leads to reactive bone remodeling, forming osteophytes, microfractures, subchondral eburnation and pseudocysts, and the exposure of the articular end of the bone.
Clinical manifestations of OA are joint pain, stiffness in the morning or after rest, pain at night, limited motion, joint deformity, occasionally synovitis, and variables degrees of inflammation. Joint pain in OA may originate not only from synovitis, but also from stretching of the joint capsule or ligaments, periosteal irritation, trabecular microfractures, intraosseous hypertension or muscle spasms.
The disruption of the proteoglycans and glycosaminoglycan aggregation is accompanied by an increase in water in the cartilaginous matrix, diminishing its rigidity. This decreased rigidity in turn increases the vulnerability of the tissue to the mechanical and chemical damage, promoting the release of Interleukin-1 (IL-1) and nitric oxide by the chondrocytes in response to the fibronectin fragments that are formed. It also increases the release of proteases with consequent collagen degradation, destabilizing the chondral matrix and further increasing water content.
The joints that are more frequently affected by osteoarthritis are, in decreasing sequence: distal interphalangeal, first carpometacarpal, proximal interphalangeal, knees, first metatarsophalangeal, and coxofemorals.
Osteoarthritis has high prevalence and is one of the main causes of pain and incapacity in elderly people. There are no specific treatments for OA, and the treatments that are available are of high cost and are only focused on controlling and diminishing the pain and inflammation associated with OA disease (i.e., obtaining symptomatic relief) and not with controlling, diminishing or eradicating the disease itself.
Mexican patent request number PA/A/2006/002927 entitled “Derivados de iminoácidos biciclicos como inhibidores de metaloproteínasas de la matríz”, describes some imino acids and derivatives thereof that may be useful in the production of pharmaceuticals for the prevention and treatment of diseases whose evolution include an increase in matrix metalloprotease activity, such as joint degenerative diseases, connective tissue diseases, periodontal disease, disorders of the locomotive system, and inflammatory or carcinogenic diseases, as well as those diseases and disorders that arise after or as a result of injuries to the joints, meniscus, kneecaps or ligaments, disruptions in healing injuries, bone metabolism disruptions, ulceration, stenosis, arthropathy, myalgia, anorexia or septic shock.
In Mexican patent request number PA/A/2004/000854 entitled “El uso de derivados de heparinoide para el tratamiento y diagnóstico de desordenes que se puedan tratar con heparinoides,” some heparinoid derivative compounds useful for preventing and treating metalloproteinase-related diseases and disorders are disclosed.
Mexican patent request number PA/a/2003/004965 entitled “El uso de la heparina de bajo peso molecular para el tratamiento de la osteoartrosis” discloses the use of heparin derivatives containing a chelating agent covalently bound to heparinoid and a paramagnetic cation metal from metal transition series (Sc, Ti, Cr, Mn, Fe, Co, Ni, Cu, Mo, Ru) or lanthanides. These derivatives are reported to be suitable for the production of drugs for certain therapeutic and diagnostic purposes, for localization of administered dose, and for supervision of treatment success of diseases such as osteoarthrosis and thrombosis.
U.S. Pat. Nos. 6,207,672 and 5,856,358 entitled “Cyclic and heterocyclic N-substituted α-iminohydroxamic and carboxylic acids” and “Mono- and disulfo-substituted anthraquinones and their use for the treatment of bone matrix disorders,” respectively, claim the use of several compounds for OA treatment.
Currently, however, there does not exist a specific treatment for OA; there are only certain treatment strategies that are frequently used to allow the mobility of the patient, or to control and diminish the primary symptoms of the disease, such as pain and inflammation.
Some options employed in order to improve mobility are:                (a) Physical medicine and rehabilitation;        (b) Weight loss when the joints that support load are affected and the patient is also overweight;        (c) Biomechanical handling such as corsets, external prosthesis, etc.Pharmacological Treatment of Osteoarthritis Symptoms        
Pharmacological treatment of the disease symptoms of OA generally includes a variety of approaches focused on controlling and diminishing the pain associated with the disease. Among such approaches are the following options:                (a) Administration of analgesics such as paracetamole and tramadole;        (b) Administration of non-steroidal anti-inflammatory drugs (NSAIDs), viscosupplementation, corticoids and/or narcotics;        (c) Orthopedic surgery; and        (d) Experimental treatments (e.g., transplant of cartilage and mesenquitomatoses cells, administration of cytokine inhibitors (IL-1, tumor necrosis factor α (TNF-α), etc.), administration of metalloprotease inhibitors, administration of nitric oxide synthetase inhibitors, administration of growth factors and administration of chondroprotectors).        
Thus, there are many treatment modalities for OA including non-pharmacological (e.g., patient education, weight control, physical and occupational therapy) and pharmacologic therapy (e.g., intraarticular steroid injections, paracetamol, topical analgesics, nonsteroidal anti-inflammatory drugs and opioid analgesics). The handling of osteoarthritis is predominantly palliative, focused in the mitigation of the symptoms such as pain and inflammation. Nevertheless, since existing therapeutic approaches do not attack the mechanism of origin OA, cartilage deterioration continues despite physical and/or pharmacological attempts to treat the disease and/or its symptoms. The most used drugs for the treatment of the osteoarthritis are the NSAIDs (Abramson S B. The role of NSAIDs in the treatment of osteoarthritis. Brandt K D, Doherty M, Lohmlander L S (Eds). Oxford University Press. 2003: 251-258; Schnitzer T J. American College of Rheumatology. Update of ACR guidelines for osteoarthritis: role of the coxibs. J Pain Symptom Manage. 2002: S24-S30), which are common analgesics that reduce pain and inflammation. This type of drug includes aspirin, ibuprofen and naproxen. They act by blocking the synthesis of prostaglandins via non-selective inhibition of the cyclooxygenase enzyme activity (“COX”; Vane J R, Bakhle Y S, Botting R M. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol. 1998, 38:97-120). Although the NSAIDs are the most widely prescribed drugs to reduce joint pain and stiffness, the inflammatory component of OA occasionally is minimal; therefore, the actual need for the anti-inflammatory effects of the NSAIDs, and thus the benefit of administering such drugs, in OA treatment is controversial. Moreover, inhibition of prostaglandin biosynthesis is directly related to many common and occasionally severe side effects including gastrointestinal bleeding, hypertension, congestive hearth failure, hyperkalemia, renal insufficiency and platelet aggregation inhibition (Zeisel S H. Regulation of nutraceuticals. Science. 1999, 285; Halsted C H. Dietary supplements and functional foods: 2 sides of a coin? Am Clin Nutr. 2003, 77:1001S-1007S; Diplock A T, Aggett P J, Ashwell M, Bornet F, Fern F B, Roberfroid M B. Scientific concepts of functional foods in Europe; consensus document. Br J Nutr. 1999, 81:S1-S27). In fact in April 2005, the U.S. Food and Drug Administration (FDA) requested to the manufacturers of NSAIDs that a warning label be included on NSAID products, alerting the consumer to the increased risk of cardiovascular events and intestinal bleeding that could accompany the use of the products. These disadvantages call for an evaluation of the risks and benefits of such therapies for OA, in comparison with the less toxic (or at least less risky) approaches.
Another type of drugs, the Cyclo-oxygenase 2 (COX2) selective inhibitors, have demonstrated analgesic and anti-inflammatory efficacies in patients with OA comparable to those of traditional NSAIDs, and an improved safety profile relative to NSAIDSs (Ramsey S D, Spencer A C, Topolski T D, Belza B, Patrick D L. Use of alternative therapies by older adults with osteoarthritis. Arthritis Reum. 2001, 45:222-227). Nevertheless, numerous reports of heart attacks and adverse cerebrovascular events have led the FDA to reevaluate the risks against benefits of COX-2 inhibitors. As a result of the FDA's analysis, the COX-2 drugs rofecoxib (marketed in the US under the brand name VIOXX®) and valdecoxib (marketed in the US under the brand name BEXTRA®) have been withdrawn from the market in the United States, after it was reported that an increase in heart attacks was observed in patients taking these drugs (Lane N E. Pain management in osteoarthritis: the role of COX-2 inhibitors. J rheumatol, 1997, 24:20-24). The COX-2 drug Celecoxib (marketed in the US under the brand name CELEBREX®) is still available, but only with serious warning labels and recommendations of being prescribed at low doses and during a limited period of time to avoid adverse effects.
In another therapeutic approach, the inflammation and moderate to severe joint pain associated with OA can be effectively relieved by intra-articular injection of corticosteroids. However, the long-term impact and safety of such injections, especially on knee anatomical structure, is still unknown. Thus, while the corticosteroids are a useful form of treatment for OA, the disadvantage is that the palliatory effect of corticosteroid injection appears to last for only 1 to 3 weeks and that such injections could themselves also lead to long-term joint damage. Other concerns associated with the use of corticosteroid injection include synovitis, cutaneous atrophy (local), and steroid arthropathy.
The use of natural glucosamine and chondroitin sulfate (as food additives) against degeneration of articular cartilage at other locations has recently received much attention. Most emphasis was laid upon the reported beneficial effect of glucosamine and chondroitin sulfate on OA of the knee, and the general conclusion was that the results were promising but the evidence insufficient to support a conclusion that such food additives were useful in the treatment or prevention of OA (Pelletier J P, Martell-Pelletier J, Raynauld, J P. Most recent developments in strategies to reduce the progression of structural changes in osteoarthritis: today and tomorrow. Arthritis Research and Therapy. 2006, 8:206).
One OA treatment that has demonstrated an effectiveness of 70% to 90% and produces excellent results is the transplantation of cultured autologous chondrocytes. This method consists of taking chondral cellular material from the patient and seeding it in a proper culture medium for its proliferation, and then, once enough cellular volume is achieved, implanting it in the damaged tissues to cover their defects (Vladimir B. Autologous chondrocyte transplantation. American Academy of Orthopaedic Surgeons Annual Meeting. 2000, pp. 1-6). Despite its promise, however, this approach to treating OA is an expensive and time-consuming procedure.
Another OA treatment that at the present enjoys high popularity involves the intraarticular application of commercially available artificial synovial fluid, such as HYALGAN® (Sanofi-Aventis US, Bridgewater, N.J.), ORTHOVISC® (DePuy Mitek, Inc, Raynham, Mass.), ARTZAL®/SUPARTZ® (Seikagaku Corpn., Tokyo, Japan) and SYNVISC® (Genzyme Corpn., Cambridge, Mass.). This substance acts only by modifying the rheology of the synovial fluid, producing an almost immediate sensation of free movement and pronounced reduction of pain in patients afflicted with OA. However, the effect of this artificial synovial fluid administration is temporary, because the material remains within the articular chamber for only about 72 hours before it is absorbed and metabolized. In addition, the main underlying problem causing OA is not corrected by such a treatment—that is, the cartilage is not repaired from articular damage. Hence, even with such a treatment which results in temporary alleviation of OA symptoms, joint deterioration continues.
Thus, it is clear that there is a need in the art for a more specific approach to treating and/or preventing osteoarthritis, which not only improves and alleviates the symptoms associated with OA but which also affects and reverses the underlying physiological causes of the disease.